MicroRNAs (miRNAs) and short interfering RNAs (siRNAs) regulate gene expression through a process termed RNA interference (RNAi). Mature miRNAs and siRNAs comprise a guide strand that is partially complementary to a target nucleic acid and an anti-guide or passenger strand that is complementary to the guide strand. Upon incorporation of the guide strand into the RNA-induced silencing complex (RISC), the guide strand base pairs with the target nucleic acid, which is then silenced by degradation and/or inhibition of translation. Several synthetic oligonucleotides are available that are able to silence specific target sequences, but they generally tend to also silence unintended targets. This nonspecific silencing is termed off-targeting or off-target effects. Off-targeting may be mediated by erroneous entry of the passenger strand into RISC. There is a need, therefore, for improved synthetic oligonucleotides that mimic the effects of short RNAs with high specificity and minimal off-target effects.